PINCH (Particularly Interesting New Cys-His protein) is a LIM-only protein consisting primarily of five LIM domains. The LIM motif, recognized in 1990 in the lin-11, isl-1 and mec 3 proteins, specifies a double zinc finger domain which has been shown to participate in protein-protein interactions. Within the LIM family PINCH has the largest number of LIM domains (five), giving rise to ten zinc fingers.
The function of LIM domain proteins as adapters and modifiers in protein interactions has been reviewed recently. PINCH likely functions as an adapter protein for signal transduction. Adapter molecules such as PINCH can control the location, assembly and function of signaling networks, and may be constitutively-anchored to a particular subcellular localization or may be recruited to a signaling site. Because PINCH is associated with .beta.1 integrin, a protein localized to the plasma membrane, it is reasonable to assume that PINCH functions as an anchoring adapter protein, targeting signaling components to sites of signal transduction at the cell membrane.
The PINCH signaling complex also contains the integrin-linked kinase (ILK), a serine-threonine kinase that associates with the cytoplasmic tails of integrins .beta.1 and .beta.3. ILK is involved in integrin-mediated signaling as well as in the .beta.-catenin/LEF-1 signaling pathway, participating in the complex signaling interactions that occur at cell-matrix and cell-cell junctions. ILK may function in crosstalk between cell-matrix and cell-cell junctions and also with components of the Wnt signaling pathway.
ILK has been shown to have oncogenic properties. ILK-over expressing cells are tumorigenic in nude mice. The mechanisms by which ILK up regulation leads to a transformed phenotype are as yet poorly understood, but the available information points to effects on the nucleus. ILK over expression leads to up regulation of specific cell-cycle associated proteins and to the translocation of .beta.-catenin from the cell membrane to the nucleus where it forms a complex with the transcription factor LEF-1. Because ILK over expression in cultured epithelial cells leads to enhanced fibronectin matrix assembly (a feature of mesenchymal cells), it is possible that ILK over expression in epithelial cells is associated with activation of mesenchymal gene expression.